Clinicopathologic features and survival in
fibrolamellar carcinoma: comparison with
conventional hepatocellular carcinoma
with and without cirrhosis
Sanjay Kakar1, Lawrence J Burgart2, Kenneth P Batts3, Joaquin Garcia1, Dhanpat Jain4
and Linda D Ferrell1
1Department of Anatomic Pathology, UCSF/VA Medical Center, San Francisco, CA, USA;2Mayo Clinic,
Rochester, MN, USA;3Abbott Northwestern Hospital, Minneapolis, MN, USA and4Yale University School
of Medicine, New Haven, CT, USA
Fibrolamellar carcinoma arises in noncirrhotic livers of young individuals and has been considered to be less
aggressive than conventional hepatocellular carcinoma. This study compares survival and clinicopathologic
features of fibrolamellar carcinoma with hepatocellular carcinoma arising in noncirrhotic and cirrhotic livers.
Clinical and pathologic features including age, gender, tumor size, stage and survival were recorded in 20
resected cases of fibrolamellar carcinoma. Survival was compared with resected hepatocellular carcinoma
without (n¼32) and with cirrhosis (n¼30). Proliferative activity was determined by immunohistochemistry for
Ki-67. In all, 12 (60%) patients with fibrolamellar carcinoma died during follow-up; the 5-year survival was 45%.
Mortality in fibrolamellar carcinoma was higher with metastatic disease at presentation (6/7, 86% vs 5/13, 39%,
P¼0.06). Age, gender and tumor size did not correlate with survival. The 5-year (45 vs 56%, P¼0.4) as well as
overall survival (40 vs 56.3%, P¼0.3) was similar in fibrolamellar carcinoma and hepatocellular carcinoma
without cirrhosis. The 5-year and overall survival in hepatocellular carcinoma with cirrhosis was 27 and 23.3%,
respectively, which was not significantly different compared to fibrolamellar carcinoma (P¼0.2). Among the
cases without metastases at presentation, 5-year survival in fibrolamellar carcinoma (62%) and hepatocellular
carcinoma without cirrhosis (57%) was significantly better (P¼0.03) than hepatocellular carcinoma with
cirrhosis (27%). The mean Ki-67 index was similar in all three groups (P¼0.1). In conclusion, fibrolamellar
carcinoma is an aggressive neoplasm with 45% 5-year survival and overall mortality of 60%. Nearly half the
patients develop lymph node or distant metastasis. The prognosis of fibrolamellar carcinoma is similar to
conventional hepatocellular carcinoma. Among nonmetastatic cases, the prognosis is better in fibrolamellar
carcinoma and hepatocellular carcinoma without cirrhosis compared to hepatocellular carcinoma with
cirrhosis. The better outcome in fibrolamellar carcinoma appears to be due to the absence of cirrhosis rather
than its distinct clinicopathologic features.
Modern Pathology (2005) 18, 1417–1423. doi:10.1038/modpathol.3800449; published online 27 May 2005
Keywords: fibrolamellar; hepatocellular carcinoma; survival; cirrhosis
Fibrolamellar hepatocellular carcinoma is a variant
of hepatocellular carcinoma with distinct clinico-
pathologic features. It occurs at a young age1–3and
lacks common risk factors for hepatocellular carci-
noma like viral hepatitis and cirrhosis.4–6Elevated
alpha fetoprotein (AFP) levels are infrequent.2,6
The defining feature of fibrolamellar carcinoma is
its triad of histologic characteristics, viz. tumor
cells with deeply eosinophilic cytoplasm, presence
of macronucleoli and abundant fibrous stroma
arranged in thin parallel lamellae around the tumor
Many studies have advocated that fibrolamellar
carcinoma is less aggressive than conventional
hepatocellular carcinoma.1,3–5,8–14Several pathology
and hepatology texts mention that fibrolamellar
carcinoma is associated with a favorable prog-
nosis.15–18However, other studies have failed to
confirm the observation of a better outcome in
Received 9 March 2005; revised 18 April 2005; accepted 19 April
2005; published online 27 May 2005
Correspondence: Dr S Kakar, MD, Department of Anatomic
Pathology, UCSF/VA Medical Center, San Francisco, CA 94121,
Modern Pathology (2005) 18, 1417–1423
& 2005 USCAP , Inc All rights reserved 0893-3952/05 $30.00
the Liver, 9th edn., Vol. 2. Lippincott, Williams and
Wilkins: Philadelphia, 2003, pp 1585–1614.
16 Sherlock S, Dooley J (eds). Malignant liver tumors.
In: Diseases of the Liver and Biliary System, 11th
edn. Blackwell Science: Malden, MA, 2003, pp
17 Rosai J. Rosai and Ackerman’s Surgical Pathology.
Mosby: Philadelphia, 9th edn., Vol. 1. 2004, pp
18 Ferrell LD. Benign and malignant tumors of the
liver. In: Odze RD, Goldblum JR, Crawford JM (eds).
Surgical Pathology of the GI Tract, Liver, Biliary
Tract and Pancreas. Saunders: Philadelphia, 2004,
19 Nagorney DM, Adson MA, Weiland LH, et al. Fibro-
lamellar hepatoma. Am J Surg 1985;149:113–119.
20 Haas JE, Muczynski KA, Krailo M, et al. Histopathol-
ogy and prognosis in childhood hepatoblastoma and
hepatocarcinoma. Cancer 1989;64:1082–1095.
21 Katzenstein HM, Krailo MD, Malogolowkin MH, et al.
Fibrolamellar hepatocellular carcinoma in children
and adolescents. Cancer 2003;97:2006–2012.
22 Hamilton SR, Aaltonen LA (eds). Tumors of the liver
and intrahepatic bile ducts. In: Pathology and Genetics
of the Digestive System. IARC Press: Lyon, 2000, pp
23 Chedid A, Ryan LM, Dayal Y, et al. Morphology and
other prognostic factors of hepatocellular carcinoma.
Arch Pathol Lab Med 1999;123:524–528.
24 Quaglia A, Bhattacharjya S, Dhillon AP. Limitations of
the histopathological diagnosis and prognostic assess-
ment of hepatocellular carcinoma. Histopathology
25 Monto A, Wright TL. The epidemiology and preven-
tion of hepatocellular carcinoma. Semin Oncol 2001;
26 Vecchio FM, Federico F, Dina MA. Copper and
hepatocellular carcinoma. Digestion 1986;35:109–114.
27 Lefkowitch JH, Muschel R, Price JB, et al. Copper and
copper-binding protein in fibrolamellar liver cell
carcinoma. Cancer 1983;51:97–100.
28 Guigui B, Mavier P, Lescs MC, et al. Copper and
copper-binding protein in liver tumors. Cancer 1988;
29 Garcia de Davila MT, Gonzalez-Crussi F, Mangkornka-
nok M. Fibrolamellar carcinoma of the liver in a child:
ultrastructural and immunohistologic aspects. Pediatr
30 Wang JH, Dhillon AP, Sankey EA, et al. ‘Neuroendo-
crine’ differentiation in primary neoplasms of the liver.
J Pathol 1991;163:61–67.
31 Caballero T, Aneiros J, Lopez-Caballero J, et al.
Fibrolamellar hepatocellular carcinoma. An immuno-
histochemical and ultrastructural study. Histopatho-
32 Zhao M, Laissue JA, Zimmermann A. ‘Neuroendo-
crine’ differentiation in hepatocellular carcinomas
(HCCs): immunohistochemical reactivity is related to
distinct tumor cell types, but not to tumor grade. Histol
33 Huang XF, Wang CM, Dai XW, et al. Expressions of
chromogranin A and cathepsin D in human primary
hepatocellular carcinoma. World J Gastroenterol 2000;
34 Orsatti G, Greenberg PD, Rolfes DB, et al. DNA ploidy
of fibrolamellar hepatocellular carcinoma by image
analysis. Hum Pathol 1994;25:936–939.
35 Wilkens L, Bredt M, Flemming P, et al. Cytogenetic
aberrations in primary and recurrent fibrolamellar
hepatocellular carcinoma detected by comparative
genomic hybridization. Am J Clin Pathol 2000;114:
36 Okada K, Kim YI, Nakashima K, et al. Fibrolamellar
hepatocellular carcinoma coexistent with a hepatocel-
lular carcinoma of common type: report of a case. Surg
Survival in fibrolamellar carcinoma
S Kakar et al
Modern Pathology (2005) 18, 1417–1423